Toxicity profile of bevacizumab in the UK Neurofibromatosis type 2 cohort

Angiogenesis inhibitors have emerged as an effective targeted therapy in the treatment of patients with many cancers. One of the most widely used angiogenesis inhibitors is bevacizumab, a neutralizing antibody against vascular endothelial growth factor. The overall risk of proteinuria and hypertension in patients with cancer on bevacizumab therapy is unclear. We performed a systematic review and meta-analysis of published clinical trials of bevacizumab to quantify the risk of proteinuria and hypertension. The databases MEDLINE (OVID, 1966 to June 2006) and Web of Science and abstracts presented at the American Society of Clinical Oncology annual meetings from 2004 through 2006 were searched to identify relevant studies. Eligible studies were randomized controlled trials of patients with cancer treated with bevacizumab that described the incidence of proteinuria and hypertension. Relative risk (RR) was calculated by using the fixed-effects model. A total of 1,850 patients were included in the 7 trials identified from the literature. Bevacizumab was associated with a significant increased risk of proteinuria (RR, 1.4 with low-dose bevacizumab; 95% confidence interval [CI], 1.1 to 1.7; RR, 2.2 with high dose; 95% CI, 1.6 to 2.9). Hypertension also was increased significantly among patients receiving bevacizumab (RR, 3.0 for low dose; 95% CI, 2.2 to 4.2; RR, 7.5 for high dose; 95% CI, 4.2 to 13.4). There was a significant dose-dependent increase in risk of proteinuria and hypertension in patients with cancer who received bevacizumab.

Angiogenesis inhibitors that target the epidermal growth factor (EGF) receptor (EGFR) and vascular endothelial growth factor (VEGF) constitute an important addition to the therapeutic armamentarium for the treatment of patients with metastatic disease. However, because the same growth factors are expressed in the kidneys, these treatment molecules have renal side effects. EGFR is expressed mainly in tubules (mainly distal and collecting segments) and mesangial and parietal epithelial cells. EGF is involved in maintaining tubular integrity and is a potent mitogen for cultured mesangial cells. Few cases of acute renal failure have been reported related to EGFR inhibitors. VEGF and VEGF receptors are still highly expressed in the kidney. VEGF is expressed in podocytes in the glomerulus, and VEGF receptors are present on endothelial, mesangial, and peritubular capillary cells. Signaling between endothelial cells and podocytes is essential for the proper development and maintenance of the filtration function of the kidney glomerulus. The most common renal class effects of VEGF antagonists are both manageable; hypertension and proteinuria commonly regressive on drug withdrawal. There was a dose-dependent increase in risk of proteinuria and hypertension in patients with cancer who received targeted therapies. Furthermore, few patients with glomerulonephritis or thrombotic microangiopathy secondary to treatment were reported. Hypertension is believed to be nitric oxide dependent, whereas proteinuria seems to be related to downregulation of podocyte tight junction protein. This article reviews data relating to hypertension and proteinuria associated with the use of these drugs.

Purpose Neurofibromatosis type 2 (NF2) is a tumor predisposition syndrome characterized by bilateral vestibular schwannomas (VSs) resulting in deafness and brainstem compression. This study evaluated efficacy and biomarkers of bevacizumab activity for NF2-associated progressive and symptomatic VSs. Patients and Methods Bevacizumab 7.5 mg/kg was administered every 3 weeks for 46 weeks, followed by 24 weeks of surveillance after treatment with the drug. The primary end point was hearing response defined by word recognition score (WRS). Secondary end points included toxicity, tolerability, imaging response using volumetric magnetic resonance imaging analysis, durability of response, and imaging and blood biomarkers. Results Fourteen patients (estimated to yield > 90% power to detect an alternative response rate of 50% at alpha level of 0.05) with NF2, with a median age of 30 years (range, 14 to 79 years) and progressive hearing loss in the target ear (median baseline WRS, 60%; range 13% to 82%), were enrolled. The primary end point, confirmed hearing response (improvement maintained ≥ 3 months), occurred in five (36%) of 14 patients (95% CI, 13% to 65%; P < .001). Eight (57%) of 14 patients had transient hearing improvement above the 95% CI for WRS. No patients experienced hearing decline. Radiographic response was seen in six (43%) of 14 target VSs. Three grade 3 adverse events, hypertension (n = 2) and immune-mediated thrombocytopenic purpura (n = 1), were possibly related to bevacizumab. Bevacizumab treatment was associated with decreased free vascular endothelial growth factor (not bound to bevacizumab) and increased placental growth factor in plasma. Hearing responses were inversely associated with baseline plasma hepatocyte growth factor ( P = .019). Imaging responses were associated with high baseline tumor vessel permeability and elevated blood levels of vascular endothelial growth factor D and stromal cell–derived factor 1α ( P = .037 and .025, respectively). Conclusion Bevacizumab treatment resulted in durable hearing response in 36% of patients with NF2 and confirmed progressive VS-associated hearing loss. Imaging and plasma biomarkers showed promising associations with response that should be validated in larger studies.